{"id":362,"date":"2014-06-25T13:21:43","date_gmt":"2014-06-25T13:21:43","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=362"},"modified":"2017-08-21T12:53:35","modified_gmt":"2017-08-21T12:53:35","slug":"primary-care-corner-with-geoffrey-modest-md-pcsk9-inhibitor","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2014\/06\/25\/primary-care-corner-with-geoffrey-modest-md-pcsk9-inhibitor\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: PCSK9 Inhibitor"},"content":{"rendered":"

probably the most exciting new drug for lipids are the PCSK9 inhibitors. i have appended below a blog from march 2012 which discusses proposed mechanism of action of these inhibitors as well as an epidemiologic study showing that those with naturally occurring PCSK9 function loss had much lower LDL levels and many fewer \u00a0coronary events. this new multicenter, multi-country study is the longest RCT to look at evolocumab, a monoclonal antibody that inhibits PCSK9, to assess its safety and efficacy (see\u00a0DOI: 10.1056\/NEJMoa131622<\/strong>). 901 hyperlipidemic patients per ATPIII were put on several different meds\/combos for 4-12 weeks, then randomization of those with CAD and LDL<100, or those without CAD but high risk if LDL<130 to either 420mg of evolocumab (subq injection) or placebo every 4 weeks.<\/p>\n

–baseline characteristics: mean age 56, 47% male, 80% white, mean LDL 95-120,<\/p>\n

results after 52 weeks, as compared to placebo group:<\/p>\n

–baseline diet,\u00a0evolocumab assoc with 55.7% reduction in LDL
\n–baseline atorvastatin 10mg,\u00a0evolocumab assoc with 61.6% reduction in LDL
\n–baseline atorvastatin 80mg,\u00a0evolocumab assoc with 56.8% reduction in LDL
\n–baseline atorvastatin 80mg + ezetimibe,\u00a0evolocumab assoc with 48.5% reduction in LDL
\n–overall level of LDL was <70mg\/dl in 82.3% of those on the\u00a0evolocumab
\n–also significant reductions in apolipoprotein B (40%), non-HDL cholesterol (50%), lipoprotein (a) (25%), chol\/HDL ratio (35%) and triglycerides (10%)
\n–and significant increases in HDL (5.4%), apo A-1 (3.0%). no change in CRP
\n–adverse effects: pretty minimal. without signif difference from placebo<\/p>\n

so, really impressive numbers. \u00a0all in the right direction. BUT, a few little details.<\/p>\n

–how does this translate into clinical events?? \u00a0we know that ezetimibe lowers LDL a lot (20%), but to no avail. we know that CETP inhibitors (torcetrapib, dalcetrapib) dramatically increase HDL (50-100%) also to no avail. even with our relatively primitive (though improving) understanding of lipids, there are differences in LDLs (the big fluffy ones have 1\/3 the coronary risk of the small dense ones — meaning for example that lowering LDL 20% but converting big ones to little ones may worsen the risk!) and HDLs (not just size, but those with apo c-III are pro-inflammatory and assoc with MORE cad. i myself have been led down the primrose path way too many times, thinking that homocysteine, vitamin E, hormone replacement, ezetimibe, CETP inhibitors, etc etc all played an important role….. \u00a0so, i really bring this new article up to show the impressive initial data but to warn about drawing any conclusions prior to real clinical data (eg ezetimibe was approved based on lipid changes, not clinical events).<\/p>\n

–and, then there’s that pesky detail of cost<\/p>\n

here is the prior blog from march 2012<\/strong><\/p>\n

2 interesting basic-science type articles on proprotein convertases: to my not-so-sophistocated understanding, these are proteins which, when cleaved and activated, affect cellular function and are often part of cellular homeostasis (like pro-insulin).\u00a0 In any event, there is one (PCSK9, which is paraprotein covertase subtilisin\/kexin 9, in case you were wondering), which degrades the hepatic LDL receptor and leads to increased levels of LDL (single point mutations which increase their activity\u00a0are associated with very high LDLs as in familial autosomal dominant hyperlipidemia).\u00a0(see\u00a0N Engl J Med 2011;365:2507-18<\/strong>).\u00a0Loss of function leads to significantly decreased LDLs, with one study showing 2.6% of black pts\u00a0have this loss of function naturally, assoc with 88% dec in coronary risk, indep of other risk factors (see\u00a0N Engl J Med 2006;354:1264-72<\/strong>).\u00a0 Some animal studies with meds to decrease function assoc with >60% dec in LDL.\u00a0 So, may be important in the future.<\/p>\n

geoff<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

PCSK9 Inhibitor […]<\/p>\n

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